Research Area. This application addresses broad Challenge Area (14): Stem Cells and specific Challenge Topic, 14-AR-102: Discovery Technologies for Multipotent and Induced Pluripotent Stem Cells from Human Skin and Musculoskeletal Tissues. Adult stem cells represent a promising resource for the development of cell based therapies to treat a broad range of diseases. Their application is not hampered by ethical concerns and they can be used in a patient tailored manner. The accessibility of skin makes a multipotent adult stem cell population known as skin derived precursor (SKP) cells a particularly attractive cell type. Limiting the development of this technology is the lack of efficient methods to derive desired physiologically active therapeutic cell fates from SKPs. The work proposed in this project will delineate small molecule and protein factors that can direct the differentiation and reprogramming of SKP cells to a desired lineage. Long term objectives include the identification of factors that facilitate the efficient derivation of myelinating Schwann cells and physiologically active neurons from human SKP cells. Transplanted Schwann cells have been shown to promote functional recovery following spinal cord injury and are believed to hold promise in the development of treatments for demyelination diseases (e.g. multiple sclerosis). Neuron progenitor cells derived from SKPs could be used in neuron replacement therapies (e.g. for the treatment of Parkinson's disease) and factors that stimulate neuron induction in SKP cells could be used therapeutically to stimulate endogenous neurogenesis for the treatment of peripheral neuropathies. Unbiased high throughput screens of large libraries (>1 million) of drug-like small molecules and arrayed collections of ~4000 secreted proteins will be performed to identify factors that facilitate the derivation of desired cell fates. The physiological utility of promising leads will be validated using relevant in vivo mouse models and electrophysiology, where appropriate. To elucidate the biological mechanisms of factors identified in these screens, targets of small molecule hits will be determined using a combination of genomic and biochemical affinity based approaches. This work will facilitate the development of therapeutic applications for adult stem cells and will lead to the identification of biological mechanisms that mediate their differentiation. In addition, success in this project will serve to provide precedence and pave the way for additional efforts to identify factors that control stem cell fate. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify molecules that facilitate the efficient derivation of therapeutic cell types from stem cells that reside in human skin. These molecules will advance the development of cell based therapies to treat a range of diseases related to the nervous system. Potential applications will be the development of cell transplantation strategies to treat spinal cord injury, multiple sclerosis, Parkinson's disease and various peripheral neuropathies.